Index

Introduction

It seems likely that primitive man wished at times to escape his reality and
most probably found some natural drug to facilitate this desire. In fact, abuse
of the coca leaf and the opium poppy is thought to have been practiced for at
least the last 3400 years (Lathrap 1976; Rosengarten 1969) and the use of peyote
may have been known as early as 1000 BC (Schultes 1938; 1940). Perhaps due in
part to the long history of opiate products, one of the first derivatives of a
natural drug to be used pharmaceutically was heroin. The acceptance of heroin as
a pharmaceutical was primal in establishing the concept that certain structural
modifications of physiologically active compounds can result in new compounds
which cause biological responses which are not only similar, but are enhanced as
compared to those of the parent compounds. Other works such as the structural
elucidation of mescaline and the preparation of N-methyl and N-acetyl
derivatives of mescaline has served to strengthen this concept and to broaden
the scope of permissible derivatives (Spath 1919). In the ensuing years much
knowledge has been gained regarding biologically useful derivatives of the
naturally occurring drugs but, most importantly, the structures of the alkaloids
and the protoalkaloids have, one by one, been elucidated. This knowledge has
then allowed researchers of recent times to deduce many of the structure
relationships associated with specific biological responses. The sum of this
hardwon knowledge allows one to produce pharmaceutically useful compounds, which
have no counterpart in nature, from off the shelf chemicals. Unfortunately there
are those people who would take this body of knowledge and, rather than use it
for the enhancement of medical science, use it for their own financial gain.
Individuals such as these have created the so-called designer drug
phenomenon.

Henderson (1986) first described a synthetic drug as one which was designed
by a clandestine chemist to produce a certain pharmacological response. However,
today designer drugs are universally understood to belong to a group of
clandestinely produced drugs which are structurally and pharmacologically very
similar to a controlled substance but are not themselves controlled substances
(Langston and Rosner 1986). The Drug Enforcement Administration (DEA) has noted
that the designer drug terminology tends to cast a somewhat glamorous aura onto
the concept, and as a result, the DEA feels that it would be wise to refer to
these compounds in some other manner and suggests the use of the term Controlled
Substance Analogs (CsA).

In October of 1987 the United States Government amended the Controlled
Substance Act in an effort to curtail the illicit introduction of new CsA's. This
amendment states that any new drug which is substantially similar to a
controlled substance currently listed under the Code of
Federal Regulations (CFR), Schedule I or II, and has either pharmacological
properties similar to a Schedule I or II substance or is represented as having
those properties, shall also be considered a controlled substance and will be
placed in Schedule I. The amendment further contains provisions which exempt the
legitimate researcher as well as compounds that are already being legally
marketed from the provisions of the amendment.

Since the CsA amendment has yet to be tested in a court of law, it is much
too early to say how successful it will be in limiting the spread of the CsA
phenomena. However, it is safe to assume that there will be those who believe
that they can manage to evade the provisions of the CsA amendment, and much of
the world has not yet even attempted to find a litigious solution to the problem
of CsA's. Therefore, an attempt to identify those CsA's which would be logical
candidates for synthesis by a clandestine chemist is still a pertinent
exercise.

Hallucinogens

A great many compounds, when taken in sufficient quantity, will alter one's
perception of reality. For the purposes of this paper, the term hallucinogen is
reserved for those compounds that are characterized by the predominance of their
actions on mental and psychic functions (Brown 1972).

Hallucinogens can be classified according to structural similarities into
four groups of compounds and into one group containing miscellaneous structures.
The classifications are: indoles, phenylalkylamines, piperidyl benzilate esters,
cannabinoids and miscellaneous.

The piperidyl benzilate esters have been extensively studied and
relationships between psychotomimetic activity and chemical structure have been
established (Abood et al. 1959; Abood and Biel 1968). The N-methyl and
N-ethyl-3-piperidyl benzilate esters are controlled substances and are listed
under the CFR Schedule I as hallucinogens. Benactyzine is a noncontrolled drug
which is used medically as an antagonist to cholinergic nerve fibers (Biel et
al. 1962). It appears that the pharmacological effects of the piperidyl
benzilate esters may not be conducive to a good trip for the user. Brown
describes the pharmacological effects by explaining how thought processes are
severely disrupted. He reports that speech is disorganized and incoherent, and
that confusion, disorientation, and amnesia occur often and may be long lasting
(Brown 1972). Perhaps these compounds should not be classified as hallucinogens
but rather as incapacitating agents. Additionally, although the pharmacological
effects of the piperidyl benzilates have been compared to those elicited by
phencyclidine (Shulgin 1969), there is no evidence to suggest any significant
abuse of these compounds. Therefore, no further discussion will be given to the
piperidylbenzilate esters.

Given the world wide ready availability of marijuana, it is somewhat
difficult to produce a viable argument for making CsA's of cannabinoids.
However, ten years ago (1978) an attempt to produce CsA's from cannabis extracts
was encountered in the Jacksonville, Florida area. In this case a concentrated
extract of cannabis had been obtained by a soxhlet extraction. The extract had
been acetylated with acetic anhydride, and in the final step, the excess acetic
anhydride removed by distillation (reference is unretrievable due to its
appearance in an underground periodical). The product contained neither
quantities of nonderivatized cannabinoid nor any identifiable plant fragments.
Since this single instance, no acetalaced cannabinoid samples have been reported
by a DEA laboratory. Therefore, this instance is assumed to represent an
isolated occurrence and as such, will serve to terminate our discussion of
cannabinoid CsA's.

Under the heading miscellaneous, one must include nearly any ingestible
compound known to man, as any substance taken at toxic levels will alter one's
perception of reality. Obviously a discussion of all such compounds as models
for CsA hallucinogens is not within the scope of this article. However, the
compound known as phencyclidine (PCP or N-(1-phenylcyclohexyl)piperidine),
although developed by Parke Davis and Company (Rochester, Michigan) as an
anesthetic, does produce psychotomimetic effects and is widely abused in the
United States. It is listed in the CFR under Schedule II, and two of its
homologs and one analog are listed under Schedule I.

Therefore, in the following discussions, the indoles, the phenylalkylamines
and PCP will be
considered as possible candidates for hallucinogenic CsA's.

Ergot Alkaloids

Lysergic acid (compound 1, Figure 1) is a tetracyclic compound, and as noted
previously, contains an indole nucleus and belongs to the family of ergot
alkaloids. Nearly all of the known naturally occurring hallucinogens have a
3-(2-ethylamino)indole contained within the molecular structure.

The assessment of a particular LSD derivative as a candidate for a future CsA
involves the consideration of several points. The most important are those
attempts made by other researchers to modify the structure of LSD while
retaining hallucinogenic activity. To date, all attempts to modify the
tetracyclic ring system have resulted in a loss of hallucinogenic activity. For
instance, of the four possible C-8 stereoisomers only the dextro isomer of LSD
is hallucinogenic (Rothlin 1957a). Modification of the amide alkyl substituents
also reduces hallucinogenic activity substantially (Usdin and Efron 1972).
Additionally, substitution with either a hydroxyl or a methoxy at the C-12 of
LSD results in a compound with no hallucinogenic activity (Usdin and Efron
1972), whereas a comparably substituted methoxyindolealkylamine appears to
always be hallucinogenic (Gessner and Page 1962). The only structural
modification which results in the maintenance of hallucinogenic activity on par
with LSD is the substitution of either a methyl or an acetyl to the indole
nitrogen (Rothlin 1957b).

The total synthesis of LSD derivatives is not simple and requires the talents
of an adept synthetic chemist (Jacobs and Craig 1934; Kornfeld et al. 1954;
Garbrecht 1959). Much of the LSD produced today uses ergotamine that is obtained
from legitimate commercial sources (Golden, L. personal communication). However,
if ergotamine becomes difficult to obtain from commercial sources, the ergot
alkaloids can be produced easily and in large quantities by cultivating strains
of the fungus Claviceps in submerged cultures (Spalla 1980). Given the fact that
structural modifications of the tetracyclic ring system are likely to result in
a product with either little or no activity, and the fact that there will never
be a shortage of ergot alkaloids for clandestine syntheses, it is quite unlikely
that the total synthesis of LSD or derivatives thereof will become commonplace
in the near term. One final point to consider is that the CFR lists LSD and all
optical, geometrical, and positional isomers of LSD under Schedule I, and
Iysergic acid and lysergic acid amide under Schedule III.

Because of previously noted pharmacodynamics and the imposing nature of a
total synthesis, the immediate precursor of a LSD derivative synthesis will most
certainly be a controlled substance, namely Iysergic acid; therefore, much of
the impetus for producing noncontrolled LSD derivatives is lost. However, if the
CsA amendment were not a consideration there would be a clear first choice via
substitution of the indole nitrogen to create either 1-alkyl or 1-acyl
derivatives. Derivatives of this type most probably fall under the purview of
the CsA amendment. The N,N-methylpropyl isomer of LSD has been the only
derivative of LSD examined by the author. Derivatives of this type might seem to
be an unlikely choice for a CsA due to a high probability of significant loss in
hallucinogenic activity. However, a reduction in hallucinogenic activity may
become acceptable to the U. S. clandestine chemist when he notes that lysergic
acid amide is listed as a Schedule III substance in the CFR; therefore,
structurally similar substances of this compound are exempted from the CsA
amendment. A lucid argument can then be made that lysergic acid
N,N-dimethylamide is derived from lysergic acid amide rather than LSD. Carrying
this theme to the next logical step one would then assume that the 1-alkyl and
1-acyl derivatives of the N,N-dimethyl isomer would also not be controlled by
the CsA amendment. At present, no known CsA of LSD has ever been encountered by
the DEA.

Indolealkylamine

All of the hallucinogenic indolealkylamines can be classified as belonging to
the family of compounds known as tryptamines and are substituted
3-(2-ethylamino)indoles (compound 2, Figure 2).

The tryptamines are a most interesting and biologically useful class of
compounds. In the human body, serotonin (5-hydroxytryptamine) functions as a
vasoconstrictor, inhibits gastric secretion, stimulates smooth muscle, and is
naturally present in the central nervous system where it is involved in
neurotransmission (Goodman and Gilman 1970). The 5-methoxy homolog of serotonin
is considered to be hallucinogenic in humans as is the 5-methoxy homolog of
gramine (3-(N,N-dimethylaminomethyl)indole) (Gessner et al. 1961). Melatonin
(N-acetyl-5-methoxytryptamine), formed by the mammalian pineal gland, appears to
depress gonadal function and is known to cause contractions of melanophores.
Bufotenine, the N,N-dimethyl homolog of serotonin, is classified as a very
weakly active hallucinogen and is noted to have extremely unpleasant
cardiovascular depressive side effects (Holmstedt et al. 1967). The O-methyl
homolog of bufotenine, N,N-dimethyl-5-methoxytryptamine (5-methoxy-DMT), is
reported to be an extremely potent hallucinogen, but it, like all other C-5
substituted indolealkylamines, is not active if taken by mouth (Brown 1972).
Both DMT and DET are well known for their hallucinogenic activity, just as both
of these compounds are also inactive if taken by mouth. The N,N-dipropyl and
diallyl derivatives are also hallucinogenic only if used either parenterally or
by inhalation at approximately the same level as DET, whereas higher homologs
abruptly become inactive (Szara and Hearst 1962). The compound 6-hydroxy-DET has
been determined to be a major metabolite of DET in man (Szara et al. 1966), and
it does not possess hallucinogenic activity (Szara 1970). Conversely, the
4-hydroxy-N,N-dimethyltryptamines (psilocin and psilocybin), are very active
hallucinogens when taken orally. The activity of psilocybin
(O-phosphoryl-4-hydroxy-DMT) when taken by mouth is not related lo the
phosphoric acid radical since the pharmacological effects of psilocin
(4-hydroxy-DMT) are identical (Horita and Weber 1961). Pharmacological
information for baeocystin (4-hydroxy-N-methyltryptamine) was not found;
however, one would expect hallucinogenic activity to parallel that of the
N-alkyl-tryptamines and thereby would expect the drug to be weakly
hallucinogenic.

It is thought that in the past most clandestine syntheses of
indolealkylamines used indole as the starting material (Speeter and Anthony
1954). A modest literature search will convince a clandestine chemist that the
use of the Fischer indole synthesis affords access to a greater variety of
indole derivatives (Huisgen and Lux 1960; Robinson 1983) as it will also reduce
the chance that law enforcement will be alerted by his purchases of essential
chemicals. Hence, in the production of indolealkylamine derivatives, the covert
chemist need not be limited by the commercial availability of appropriate indole
precursors.

Relative to those which lack an aryl ring substitution, there is no doubt
that the activity of psilocybin/psilocin upon ingestion is due to an enhancement
of gastrointestinal absorption which, in turn, must be structurally related to
the presence of the C-4 hydroxyl substitution. Therefore, if the CsA amendment
were not a consideration, derivatives derived from psilocin would be the obvious
first choice. These derivatives are the 4-hydroxy-N,N-alkyl homologs starting
with N,N-dimethyl, N,N-methyl-ethyl, and on to N,N-diallyl to give a total of 10
possible derivatives. As is also the case for hallucinogenic phenylalkylamines,
alkyl substitution, not to exceed a C-3 moiety, at the position alpha to the
side chain nitrogen generally will maintain hallucinogenic activity. This brings
the total possible number of hallucinogenic CsA's of psilocin to 40. A somewhat
removed second choice would be the same series of derivatives in conjunction
with either acetylation or methylation of the indole nitrogen. This would then
bring the total number of the possible 4-hydroxy substituted tryptamine CsA's
(less one for psilocin) to 119.

The 5-methoxy derivatives of gramine and serotonin are first choices for
future CsA's when considering the new U. S. amendment. Substitution at the alpha
carbon on the side chain will probably maintain psychotropic activity only for
serotonin derivatives. Hence, allowing only a methoxy substituent at the aryl
C-5 position, and a substitution at the carbon alpha to the nitrogen (the
nitrogen being any combination of hydrogen, methyl, ethyl, n-propyl, and allyl)
75 CsA's can be obtained. Then substitution of the indole nitrogen with either
methyl or acetyl brings the total number of possible CsA's that can be
argumentatively related to serotonin to 225.

An additional series of compounds that could serve as future CsA's under U.
S. law are those which are substituted with alkyl groups at the carbon alpha to
the side chain nitrogen. Recently, a commercially available tryptamine which has
an ethyl moiety substituted at the alpha carbon has become the newest U.S.
tryptamine CsA. Known as ET in the illicit CsA drug market is
3-(2-amino-butyl)indole (etryptamine, monase by Upjohn (Kalamazoo, MI); compound
3, Figure 3). Because ET does not appear in either Schedule I or II of the CFR
and is a legally marketed product, ET and derivatives thereof are exempted from
control under the CsA amendment. Pharmacokenitic data on ET indicates that it is
a monoamine oxidase inhibitor (Govier et al. 1953; Klein and Davis 1969) and
psycho-energizer (Robie 1961; deHaen 1964). Hence, ET could produce some degree
of hallucinogenic activity in man. In 1986 ET was reported as the she causative
agent in a fatal overdose in Duesseldorf, Germany (Daldrup et al. 1986). This
may be one of the few times that a CsA has originated outside of the U. S. The
sample of ET which was submitted to our laboratory appears to have been obtained
from the Aldrich Chemical Company ($48.05/100 gm; Milwaukee, WI). Unfortunately,
it is not yet clear if ET is actually the substance which is producing the
biological response being sought by the illicit user. It is the case that the
sample of ET we examined and the batch of ET which the Aldrich Chemical Company
is presently selling contains a major quantity (about 30%) of the agent shown in
Figure 4 which could also be a hallucinogen (Turner 1963; Naranjo 1967).

Nomenclature for this possible hallucinogen can either be
1-methyl-3-ethyl-1,2,3,4-tetrahydro-harmane, or
2,2-dimethyl-4-ethyl-2,3,4,5-tetrahydro-[beta]-carboline. The creation of this
substance most probably occurred after synthesis and during the purification of
ET. Under anhydrous conditions, the reaction of acetone and ET would give the
correponding enamine which could then undergo a Mannich condensation to yield
the hallucinogen (Whaley and Govindachari 1951; Shoemaker et al. 1979). The
compound 2-methyl-8-methoxy-4,5-dihydro-[beta]-carboline (harmaline) is
considered to be a hallucinogen (Hochstein and Paradies 1957) as well as a
monoamine oxidase inhibitor (Burger and Nara 1965). On the other hand, the
compound 2-methyl-8-methoxy-2,3 4,5-tetrahydro-[beta]-carboline is classified as
a tranquilizer (Usdin and Efron 1972). We were not able to attain any literature
whatsoever on the hallucinogen shown in compound 4 (Figure 3), much less any
pharmacokenetic data. Hence, due to the apparently unpredictable pharmacological
behavior of structurally similar [beta]-carboline derivatives, I will not
speculate as to the pharmacological properties of said substance.

Phenylalkylamines

As was observed for the simple indole alkaloids, there are several simple
phenylalkylamines which play important roles in the normal biological function.
Some of these are tyrosine, 3,4-dihydroxyphenylalanine (DOPA),
3,4-dihydroxytryptamine (dopamine), and norepinephrine. The naturally occurring
hallucinogenic protoalkaloid, mescaline, is
2-(3,4,5-trimethoxyphenyl)ethylamine. Structural modifications which impart
hallucinogenic activity to phenylethylamines have een studied and a considerable
quantity of that data is easily retrieved. The following constitutes a brief
review of some of the most salient concepts relative to hallucinogenic activity
chemical structure relationships within the family of phenylethylamine
derivatives.

It has been found that the addition of methoxy moieties to the aromatic ring
of a phenylethylamine, in general, produces compounds that are psychotomimetic
(Shulgin et al. 1969). Further, it has been noted that the methylenedioxy moiety
can be used in the place of two adjacent ring substituted methoxy groups with
C-3,4 substitution providing the most potent psychotogens (Alles 1959; Shulgin
1964; Naranjo et al. 1967; Braun et al. 1980a). Historically
3,4-methylenedioxyamphetamine (MDA) has probably been the most consistently
abused psychotomimetic phenylethylamine. Amphetamine and methamphetamine are
adrenomimetic at low to moderate dose levels; however, at high dose levels they
also become psychotomimetic in man (Liddel and Weil-Malherbe 1953; Connell
1958). Additionally, it has been found that the addition of an [alpha]-alkyl
moiety (up to C-3) (Snyder and Richelson 1970) to methoxyphenylethylamines
results in an increase in hallucinogenic activity and, alkyl only substitutions
to the aromatic ring tend to result in a gradual loss of central activity which
can be related to the increasing size or the alkyl group (Marsh and Herring
1950; Harris and Worley 1957). Braun et al. (1980b) has determined that a
gradual decrease in psychotomimetic activity also occurs with the increasing
size of a N-alkyl substituent. Braun also noted that upon N,N-dialkyl
substitution an abrupt and significant loss of hallucinogenic activity occurs,
whereas N-hydroxy substitution maintains activity.

The bases of structure-activity relationships as determined by aromatic ring
substitutions are not obvious. For instance, mescaline has relatively prominent
psychotomimetic properties but 3,4-dimethoxyphenylethylamine
(3,4-dimethoxydopamine) is not considered to be psychotogenic, and the
hallucinogenic potency of 3,4-dimethoxyamphetamine is less than that of
mescaline (Hollister and Friedhoff 1966). On the other hand, the hallucinogenic
potency of 3,4-methylenedioxyamphetamine is approximately three times that of
mescaline (Braun et al. 1980b). Also, tyramine (4-hydroxyphenylethylamine) is
devoid of hallucinogenic activity, but 4-methoxy-tyramine is weakly
hallucinogenic (Smythies et al. 1969). However, 2-methoxymethamphetamine has no
known hallucinogenic activity (Usdin and Efron 1972), and the
4-methoxyphenyl-[alpha]-methylethylamine (4-methoxyamphetamine) has five limes
the psychotropic activity of mescaline (Shulgin 1970). To complicate the
situation further, one work reported the synthesis of 4-substituted
methamphetamine derivatives using both ring activating and ring deactivating
substituents of quite different atomic volumes, and found hallucinogenic
activity present for all derivatives. The compounds in question are 4-bromo-,
4-amino-, 4-chloro-, 4-nitro-, 4-iodo-, and 4-hydroxymethamphetamine (Knoll et
al. 1966). It is a little surprising that substituents of such radically
different atomic volumes and electronegativities would all give 4-substituted-
phenylisopropylamine derivatives having psychotropic activity. In contrast,
another study of hallucinogenic activity as a function of aromatic ring
substitution, found the compound 2,5-dimethoxy-4-methylamphetamine to be some
eighty times more potent than mescaline but upon going to the 4-ethyl
derivative, quite a trivial change, nearly all hallucinogenic activity was
supposedly lost (Shulgin 1969). Despite these seeming inconsistencies, many of
the necessary structural requirements for producing hallucinogenic
phenylethylamine can be understood by noting the common structural features of
these psychotogens. The structure activity relationships noted above can be
found in a single source review article by Shulgin (1970).

The following phenylalkylamines are listed under Schedule I of the CFR as
hallucinogens:

4-bromo-2,5-dimethoxyamphetamine (DOB)

2,5-dimethoxyamphetamine (DMA)

4-methoxyamphetamine (PMA)

5-methoxy-3,4-methylenedioxyamphetamine (MMDA)

4-methyl-2,5-dimethoxyamphetamine (DOM, STP)

(MDA)

3,4-methylenedioxymethamphetamine (MDMA, ecstasy)

3,4,5-trimethoxyamphetamine (TMA)

2-(3,4,5-trimethoxyphenyl)ethylamine (mescaline)

The majority of the hallucinogenic phenylethylamines which are presently
controlled under U. S. law were first encountered in a relatively short period
of time in the latter part of 1960. Since that time the emergence of new CsA's
of psychotogenic phenylethylamines has continued but at a much reduced pace.
Starting in 1972, several samples of MDMA were analyzed by DEA laboratories.
Apparently MDMA was readily accepted by the user and abuse has continued to
increase. Presently in the U. S. and Canada there are at least four other CsA's
of psychotogenic phenylethylamines in the illicit market. These are
N-hydroxy-3,4-methylenedioxyamphetamine (N-hydroxy MDA), N-ethyl MDA (EVE,
MDEA), 4-ethoxy-2,5-dimethoxyamphetamine (MEM) (Avdovich et al. 1987), and
4-bromo-2,5-dimethoxyphenylethylamine (DBMPEA) (Sapienza, E personal
communication; Allen, A. personal communication). Upon placing MDMA under legal
controls, the N-ethyl homolog of MDA (EVE) was immediately introduced as a
replacement for MDMA. However, it seems that EVE has not been well accepted by
the user, apparently because EVE has a lower potency than MDMA; therefore
requiring a larger dose to produce psychotropic effects and often resulting in
making the user ill (Jordan 1986).

Assuming the ready availability of the appropriate chemical precursors, and
assuming a lack of concern for the legal provisions enacted by governments for
the purpose of controlling CsA's, choices for CsA's of ring substituted
phenylethylamine psychotogens are numerous. Previously cited literature provides
many such CsA possibilities with at least ten aromatic ring substituted
amphetamines (compounds numbered 5-15, Figure 4) having potencies greater than
mescaline (compound 5). Other CsA's can be obtained from compounds 6 through 15
by modification of the [alpha]-alkyl side chain to either C-2 or C-3 alkyls, and
mono-substitution or the nitrogen with either hydroxy or short chain alkyl.
These modifications result in a total Of 160 possible CsA's based only upon the
ring substitutions of the aforementioned compounds. Additionally, tile ring
substituted phenylisopropylamines which are presently controlled substances, can
be modified in the same manner, and after excluding controlled substances and
N-hydroxy MDA, there are 118 more possible derivatives, giving a total of 278
possible new CsA's. Each time a new ring substitution is introduced, such as
MEM, then this number is increased by 16.

If the U. S. CsA amendment is a consideration, then psychotomimetic
phenylethylamines could be created from compounds which are structurally related
to dopamine, adrenaline
(N-methyl-3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine), and norepinephrine
(3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine). A case in point is the compound
macromerine, N,N-dimethyl-3,4-dimethoxyphenyl-[beta]-hydroxyethylamine, a known
psychotogen (Hodgkins et al. 1967). Some other compounds which could be used as
CsA models are synephrine (N-methyl-4,[beta]-dihydroxyphenylethylamine),
phentermine ([alpha],-[alpha]-dimethylphenylethylamine), 4-chlorophentermine,
mephentermine (N,[alpha],[alpha]-trimethylphenylethylamine), phenelzine
(phenylethylhydrazine), and tranylcypromine (2-phenylcyclopropylamine).
Structural modifications of these compounds could provide quite a few additional
CsA's. Because of the sheer size of the task, no attempt was made to determine
the total number of possible CsA's that could be derived by using these
compounds as models. How ever, the magnitude of the possibilities become evident
when one calculates tile possible CsA's which, could be obtained using just
dopamine (compound 16, Figure 5) as the model compound, as is demonstrated in
the following paragraph.

The total number of possible CsA's were limited by the following
considerations:

ring substitution at C-3,4 is dimethoxy

ring substitution to sites C-2,5,6 were limited to combinations of CH3-,
Br-, Cl-, and CH3-,

substitution on the amine nitrogen and the alpha carbon were limited to
the following:

of the three ring sites available for substitution, no more than two
were allowed for any given structure

single substitution on the ring at C-2 to give 2,3,4-trisubstituted
derivatives was disallowed

mixed halide structures were excluded

ring substitutions which would result in any derivative which is
presently a controlled substance were disallowed.

Given these considerations there are 47 structures which can be drawn. Each
one of these can then exist as 16 derivatives obtained by substitution as shown
above at the alpha carbon and nitrogen. The multiplication product of these two
values provides the total number of possible hallucinogenic CsA's (752) which,
one could argue, are structurally related to dopamine.

Research targeted at the determination of structure-psychotropic activity
relationships has waned in recent years. Perhaps in future years it will be the
clandestine chemist who will fill in the blanks.

Phencyclidine

The synthesis of phencyclidine (PCP) was first reported in 1958 (Chen 1958)
and patent rights were granted to Parke, Davis & Co. in 1960 and 1963 for
medical use as an anesthetic (Parke, Davis & Co. 1960; 1963). PCP first came
to the attention of DEA, then the Bureau of Narcotics and Dangerous Drugs, as a
drug of abuse in the latter part of the 1960's. Pharmacologically, PCP has been
described as a pseudo hallucinogen which has many of the characteristics of a
depressant drug (McGlothlin 1971). Without question, PCP deserves a special
niche in any discussion of drugs of abuse if for no other reason than the
notoriously bizarre effects it has been known to have upon some of the abusing
population (Peterson and Stillman 1978).

The now so very familiar synthesis using 1-(1-piperidyl)cyclo-hexyl
carbonitrile and phenyl Grignard reagent was published by Maddox et al. in 1965
and, either fortunately or unfortunately depending upon one's point of view, the
accompanying pharmacological data was useless as it could not be correlated to
the compounds synthesized (Maddox et al. 1965). However, pertinent literature is
not hard to find as both the original U. S. patent (Godefroi et al. 1963) and
later studies have provided a pharmacological basis for the production of CsA's
of PCP (Kalir and Pelah 1967; Kalir et al. 1969).

It does not appear to be possible for one to generate a CsA model structure
that will not fail under the CsA amendment provision which stipulates that the
term "controlled substance analogue" means a substance-the chemical structure of
which is substantially similar to the chemical structure of, in this case, PCP.
This is the result of the fact that a one carbon separation between an aryl
system and the amine nitrogen, and the fact that the central carbon between
these moieties is in a ring system appear to be principal requirements for
PCP-like pharmacological activity. Other activity structure relationships
are:

to maintain potency N,N-dialkyl substitutions should be either piperidino
or pyrrolidino ring systems

N-ethyl is the most potent N-alkyl monosubstitution and potency falls off
rapidly with either an increase or decrease in the alkyl chain size

substitution on the beta carbon of either the cycloalkyl or the
cycloalkylamino rings will most likely be synthetically difficult due to
steric considerations.

Because of factors noted above, there appears to be a relatively small
probability of a PCP CsA appearing in the illicit marketplace that will not fall
under the purview of the U. S. CsA amendment. However, it is also the case that
under U. S. law there is a reporting requirement placed upon the purveyors of
piperidine. Since the implementation of the piperidine reporting requirement it
has become much more difficult for the clandestine chemist to safely acquire
this chemical precursor of PCP. Therefore, a market force has been introduced
that will almost certainly result in the production of PCP CsA's which will not
contain a simple piperidino moiety. This thought, taken with the previously
discussed activity-structure relationships, allows one to suggest the 50
structures depicted in Figure 6 as being representative of future CsA's of PCP.
Of these 50 compounds, two have already been placedin the CFR Schedule I:
N,N-(1-phenylcyclohexyl)-ethylamine and N-(1-phenylcyclohexyl)-pyrrolidine.

Stimulants

Relative to medical usage, a stimulant is defined to be an agent that arouses
organic activity, strengthens the action of the heart, increases vitality, and
promotes a sense of well being. However, as per the medical definition, the
effects produced by a stimulant may not be a very accurate term for the effects
sought by those who abuse these compounds. For instance, at dose levels usually
equated with heavy abuse, both amphetamine (Hampton 1961; Angrist et al. 1969)
and methamphetamine (Liddel and Weil-Malherbe 1953) are thought to be
psychotogenic. Therefore, several of the amphetamines could be discussed as
hallucinogens; however, it seems most likely that a substantial portion of the
abuse of stimulant drugs is performed with the intention of inducing a state of
euphoria (Brown 1972). Historically, the abuse of stimulants (euphoriants) has
been largely confined to amphetamine, derivatives thereof, and cocaine. Some of
the amphetamine derivatives which have been controlled under U. S. law are
methamphetamine, N-ethylamphetamine, fenethylline, phenmetrazine (preludin),
phendimetrazine, benzphetamine, chlorphentermine, clortermine, diethylpropion,
methylphenidate, pemoline, and amphetamine. Other derivatives of amphetamine
which have been encountered in samples submitted to DEA laboratories, but have
not yet been brought under legal controls, are bis-methamphetamine (compound 18,
Figure 7), fencamfamine (compound 19, Figure 7) (Nied and Smith 1982),
N,N-dimethylamphetamine (dimephenopan; compound 20, Figure 7) (Allen, A.
personal communication), and an analog of pemoline, 4-methylaminorex (U4EUH)
(compound 21, Figure 7) (Inaba and Brewer 1987). Since pemoline is listed under
Schedule IV of the CFR and 4-methylaminorex is clearly an analog Of pemoline, it
falls outside of the guide-lines set forth in the CsA amendment; therefore,
4-methylaminorex is not controlled under U. S. law. It is equally clear that
bis-methamphetamine and N,N-dimethylamphetamine do fall under the CsA guidelines
and would be considered controlled substances under tile CsA amendment. However,
it may be that N,N-dimethylamphetamine may not enjoy a long history in the
clandestine market as at least one work states that it is considerably less
potent than methamphetamine (Schaeffer et al. 1975).

Most of the adrenomimetic activity-structure relationships were delineated in
the previous discussion on psychotomimetic phenylethylamines. The principle
difference between the pharmacological action, as related to structure for these
two classes of compounds, is determined- by the nature of the substituents on
the aryl system. In general it is noted that substituents on the aryl system
which are orthopara directors tend to produce psychotogenic compounds with
methoxy substituents often producing the most pharmacologically active
hallucinogens. However, there are several exceptions to this general statement,
not the least of which is exemplified by substitution on the phenyl ring of the
electrophilic hydroxy moiety which in nearly every case either eliminates or
greatly reduces hallucinogenic activity. On the other hand, adrenomimetic
activity is clearly enhanced by branching of phenylethylamine at the carbon
alpha to the amine nitrogen and is maintained at reasonable levels by
substitution to the nitrogen as shown in table II. Both N-ethylamphetamine and
N,N-dimethylamphetamine have appeared in the illicit market and clearly follow
the points made above. However, a market factor has been introduced by the fact
that phenyl-2-propanone (P2P) has been listed under the CFR as a Schedule II
substance. Hence, it makes little sense for the clandestine chemist to produce
CsA's of phenylethylamines which have potencies that are less than
methamphetamine if he is going to produce his CsA's in a synthesis that uses
P2P. The recent illicit use of 4-methylaminorex may well be the result of the
clandestine chemist trying to circumvent the legal problems associated with P2P.
On the other hand, the sum total of methamphetamine still being covertly
produced suggests that the control of P2P has not appreciably reduced the drug's
availability in the illicit marketplace.

As before, if the chemist is not concerned about the CsA amendment, the
structural possibilities offered by Table II, less the three controlled
substances that are included, provides for thirteen possible future stimulant
CsA's. It would seem that the single most logical next stimulant CsA would be
N-methyl-[alpha]-ethylphenylethylamine. This compound should be
pharmacologically very similar to methamphetamine and synthesis could employ
1-phenyl-2-butanone instead of P2P. Alternatively, the use of
1-(4-fluorophenyl)propan-2-one, in place of P2P, would almost certainly give a
product with adrenomimetic properties, and may in fact be considerably more
potent than methamphetamine.

The clandestine chemist of limited chemical sophistication may not notice the
structural similarity of such compounds as methylphenidate (compound 22, Figure
8), phenmetrazine (compound 23, Figure 8), 4-methylaminorex (compound 21), and
amphetamine (compound 24, Figure 8). If he does recognize the constancy of the
phenylisopropylamine substructure in these compounds he may well explore the
literature in an effort to determine the structural outer limits for the
phenylisopropylamine stimulants. At what may be near these structural outer
limits he will find a class of compounds which are correctly referred to as
conformationally rigid phenylethylamines. Some of the conformationally rigid
phenylethylamines are fencamfamine (compound 19), tranylcypromine
(2-phenylcyclopropylamine) (compound 5, Figure 9), 2-phenyl-cyclohexylamine
(compound 26, Figure 9) (Smissman and Pazdernik 1973), 2-amino-3-
phenyl-trans-decalin (compound 27, Figure 9), and 2-aminotetralin (compound 28,
Figure 9) (Barfknecht et al. 1973). The potency of most of these compounds is
highly dependent upon stereochemistry. Those isomeric forms which most closely
approximate the anti periplanar conformation observed for amphetamine in
solution are the most potent stimulants. Hence, transtranylcypromine is
considerably more potent than is the cis isomer (Grunewald et al. 1976). The
most active isomer of these compounds does not approach the potency of the
simple phenylisopropylamines. Given this reduction in potency for the most
active isomers one would think that, in order to obtain amiable product for the
illicit market, a stereo specific synthesis would be required. This feature,
along with a lowered potency for even the more active isomers, may very well
exclude the conformationally rigid phenylethylamines from the synthetic
repertoire of the surreptitious chemist. Hence, it is a reasonable expectation
that those conformationally rigid phenylethylamines which will be abused in the
future will be obtained by diversion of limit supplies rather than by
clandestine syntheses.

Unfortunately, it seems to be an axiom that any compound which has any
possibility of altering man's perception of himself or his surroundings will at
some time be abused. Propylhexadrine, although not an extreme example, is
nevertheless an example of a compound which has been abused although adrenogenic
potency is far less than that of methamphetamine (Garriott 1975). Therefore, one
must expect some abuse of the conformationally rigid phenylethylamines to occur.
It would be my guess however, that the extent of such abuse will never be
large.

The parent structure for 4-methylaminorex has been known since 1889 (Gabriel
1889) and many derivatives thereof have been studied for pharmacological
activity. Pemoline (2-amino-5-phenyl-2-oxazolin-4-one) (Traube and Ascher 1913;
Howell et al. 192) is presently a controlled substance in the U. S., is
classified as a stimulant, and is listed under Schedule IV of the CFR. Poos
(personal communication) synthesized and performend pharmacological studies for
some twenty seven 2-amino-2-oxazoline isomers of which aminorex and
4-methylaminorex were two. In this work, aminorex and 4-methylaminorex,
regardless of the steroisomer employed, were found to have anorectic activity on
par with d-amphetamine. However, adrenomimetic activity of 4-methylaminorex was
determined to be less than that of amphetamine and similar to phenmetrazine
(Patil and Yamauchi 1970). It has been suggested that the effectiveness of
stimulant drugs as appetite suppressants are the result of the fact that the
user forgets to eat and that this behavior is in direct proportion to the
adrenomimetic activity of the drug (Cutting 1969). Contrary to previously cited
work this suggests that aminorex may in fact be as potent an adrenomimetic as
amphetamine. In any case, Poos (personal communication) highlighted eight
compounds which may have adrenomimetic activity similar to those of amphetamine
and methamphetamine. Shown in Figure 10 and listed in decreasing order of
anoretic activity they are compounds:

29) 2-amino-5-(4-fluorophenyl)-2-oxazoline

30) 2-amino-5-(4-Chlorophenyl)-2-oxazoline

31) 2-amino-5-(3-trifluoromethylphenyl)-2-oxazoline

32) 2-amino-5-(4-bromophenyl)-2-oxazoline

33) 2-amino-5-phenyl)-2-oxazoline [aminorex]

34) 2-amino-5-(4-trifluoromethylphenyl)-2-oxazoline

35) 2-dimethylamino-4-methyl)-5-phenyl-2-oxazoline

36) 2-amino-4-methyl-5-phenyl-2-oxazoline [4-methylaminorex]

Although not mentioned in this work, one would immediately assume that the
4-fluoro- and 4-chloro- phenyl derivatives of compounds 35 and 36 would also
have significant anoretic activity.

Given the astoundingly simple synthetic process required to produce these
compounds, and the fact that the 4-halogen substituted aryl derivatives would
require precursors unlikely to titillate the interest of law enforcement
agencies, these compounds will most probably be made in future clandestine
syntheses. It is also conceivable that some enterprising clandestine chemist
will wonder if appropriately substituted methoxy derivatives will have
psychotomimetic properties.

The literature contain many references to stimulant drugs of variant
structures which may not spark the interest of the less knowledgeable
clandestine chemist. However, nearly all of these compounds can be accessed
through literature searches for either derivatives of phenylethlamines or
stimulant compounds. Several compounds which serve as examples are fenmetramid
(Ippen 1968), prolintane, 1-([alpha]-propylphenylethyl) pyrrolidine (Heinzelman
et al. 1960; Hollister and Gillespie 1970), pyrovalerone
(1-(4-methylphenyl)-1-oxo-2-pyrrolidino-n-pentane) (Heinemann and Vetter 1965;
Heinemann and Lukacs 1965), N,3,3-trimethyl-1-(m-tolyl)-1-phthalanpropylamine
(compound 37, Figure 11)(Gill et al. 1970), zylofuramine
([alpha]-benzyl-n-ethyltetrahydro-D-threo-furfurylamine) (Harris et al. 1963), a
series of N-substituted phentermine compounds (Borella et al. 1970),
4-hydroxyamphetamine (Mannich and Jacobsohn 1910; Hoover and Hass 1947a,b),
N-methylephedrine (Smith 1927), nylidrin,
N-(1-methyl-3-phenylpropyl)-2-hydroxy-2-(4-hydroxyphenyl-l-methyl-ethylamine
(Treptow et al. 1963), pheniprazine, [alpha]-methyl-phenylethyl hydrazine
(Zbinden et al. 1960), and N,N-diethyl-2-phenylcyclopropylamine (SKF). All of
these compounds are derivatives of phenylethylamine with the exception of
compound 37 which is a 3-phenyl-3-propylamine substituted onto a phthalane at
C-1. A number of closely allied derivatives of this compound have been examined
and are classified as weak stimulants.

Fenmetramide is noteworthy in that it is a 2-one derivative of phenmetrazine.
Any and all of these compounds are subject to abuse; however, the synthesis of
simple phenylethylamine derivatives would not appear to offer the clandestine
chemist any advantage over the synthesis of methamphetamine. The reasons for
this statement are that pharmacological studies have not identified other
phenylethylamine structures with stimulant activity appreciably greater than
methamphetamine and that either P2P or the [beta]-hydroxyphenylisopropylamines
are the preferred precursors. However, in any case, the U. S. CsA amendment
should apply for all compounds containing the phenylethylamine substructure.

The stimulant drugs phenmetrazine (preludin; compound 23) and methylphenidate
(ritalin; compound 22) are controlled under Schedule II of the CFR. These
compounds rank approximately half-way between caffeine and amphetamine in
potency (Meier et al. 1954; Tripod et al. 1954a; Gruber et al. 1956). The
published synthesis of phenmetrazine, which would seem to be most amenable to
the clandestine laboratory, is given in the work by Otto (Otto 1956). The
reaction involves the acid-catalyzed cyclization of N-hydroxyethylnorephedrine
(N-hydroxyethylphenylpropanolamine). However, this reaction places severe limits
on the production of CsA's because suitable precursors are limited. For
instance, phenmetrazine CsA could be prepared from compounds such as
N-ethyl-2,2-hydroxyphenyl-1-methylethylamine, 1,1-hydroxyphenyl-2-aminobutane,
etc, but limited commercial availability would generally require synthesis of
these compounds. Additionally, the product CsA would clearly be perceived, even
by the untrained, as being structurally similar to phenmetrazine and thereby
would be a controlled substance under the CsA amendment. Further, the
corresponding phenylethylamine which could be made from these precursors,
although also under the purview of the CsA amendment, would most probably have
greater adrenergic activity than the phenmetrazine derivative. Hence,
clandestine production of phenmetrazine CsA's would most likely be an uncommon
event.

Pipradrol (compound 38, Figure 12) is a controlled substance under CFR
Schedule IV and can be considered to be an analog derivative of methylphenidate.
Methylphenidate can be synthesized by the method of Hartmann and Panizzon
(1950). The product exists as two diastereoisomeric enantiomer pairs, one of
which is the active stimulant, threo-dl-methylphenidate (Weisz and Dudas 1960),
while the other is inactive as a stimulant. Threo-methylphenidate accounts for
only 20% of the final reaction product (Rometsch 1958;1960). The synthesis of
pipradrol may be more amenable to the clandestine laboratory as it is a
relatively simple synthesis and isolation of the final product is
straightforward. An appropriate C-2 substituted, N-protected piperidine is a
suitable precursor for what is essentially a two step synthesis (Tilford et al.
1948; Werner and Tilford 1953). Numerous derivatives of methylphenidate and
pipradrol have been synthesized with the result that structure activity
relationships have been well defined (Scholz and Panizzon 1954; Tilford and Van
Campen 1954; Heer et al. 1955; Fabing 1955; McCarty et al. 1957; Sheppard et al.
1960; Belleau 1960; Winthrop and Humber 1961; Portoghese and Malspeis 1961;
Wilimowski 1962; Lachman and Malspeis 1962). There is little incentive, beyond
the not inconsiderable pressure of an already existing and ready market, for
producing clandestine CsA's of methylphenidate. However, there are a number of
pipradrol derivatives described in the last cited references which are suitable
for clandestine production. A best bet for a future CsA is the most potent
adrenomimetic compound in this series, 2-diphenylmethylpiperidine (compound 39,
Figure 12) (Tripod et al. 1954b), which is estimated to be as potent as
methamphetamine (Sury and Hoffmann 1954). In a very similar article to this
paper, "Drugs of Abuse in the Future," Shulgin (1975) suggested that
levophacetoperane (compound 40, Figure 12) could well be a future clandestine
CsA. However, this compound shares the same limitations for clandestine
synthesis as does methylphenidate, in that only one diastereoisomer is active
(Jacob and Joseph 1960) and it is less potent than methylphenidate (Dobkin
1960).

Although the phenylisopropylamine substructure is an integral part of most
known stimulants, the well known and much abused stimulant, cocaine, does not
share this structural feature. The cocaine molecule instead compares more
closely to the structure of atropine. The synthesis of cocaine has recently
been revisited by Casale and many of the procedural techniques are explained in
sufficient detail so that any competent organic chemist can now make the C-3
equatorial cocaines (Casale 1987); however, it is still a tedious and demanding
synthesis, and in my opinion will only be encountered on rare occasions in
clandestine laboratories. The particular pharmacological behavior of cocaine is
unquestionably due in major part to the stereochemistry of the molecule as
determined by the fused bicyclic tropane ring system (Clarke et al. 1973). Given
the present difficulties associated with the synthesis of the tropanes and the
ready availability of the natural product, it is unlikely that a synthetic CsA
of this compound will appear in the near future. However, it is the case that
certain modifications of natural cocaine can result in products having
substantially greater potencies than cocaine. The compounds
2-carbomethoxy-3-(4-fluorophenyl)tropane and 2-carbomethoxy-3-phenylnortropane
are both some 60 times more potent than cocaine (Clarke et al. 1973). These
compounds could well be of interest to some clandestine chemists as taking one
kilogram or cocaine and converting it into a product some sixty times more
potent would obviously be quite cost effective.

In "Drugs of Abuse in the Future," Shulgin (1975) directed attention to
another stimulant which also does not contain the phenylethylamine substructure
and, in fact, is reminiscent of the depressant glutethimide. The compound is
known commercially as bemegride, 4-ethyl-4-methylpiperidine-2,6-dione, and was
first synthesized by Thole and Thorpe in 1911 (Thole and Thorpe 1911). The
principal medical use is as an analeptic in barbiturate poisoning. As a
stimulant, bemegride is approximately equal to phendimetrazine and pemoline in
potency. Although glutethimide and bemegride are structurally similar, their
pharmacokinetics are diametrically opposed. Hence, bemegride cannot be described
as a CsA. Bemegride, by virtue of being a stimulant, has an obvious potential
for abuse, although under the conditions of abuse, rather large quantities of
the drug will be required. Increasing the possibility of bemegride abuse are the
facts that the synthesis of the compound is not difficult and, of course, does
not use either a controlled or watched substance as a precursor (Benica and
Wilson 1950).

Sedatives-Depressants

Depressants include such diverse chemical entities as methaqualone,
5,5-disubstituted barbituric acids, glutethimide and methyprylon,
benzodiazepines, chlorhexadol, chloral hydrate, paraldehyde, meprobamate, and
ethyl alcohol to name a few. Historically in the U. S., the abuse of
depressants, alcohol aside, has been in major part confined to the barbiturates,
methaqualone, and the benzodiazepines. Barbiturate abuse peaked in the mid
1970's and has since become near nonexistent, in part no doubt, to the well
deserved bad press that the barbiturates garnered. The abuse of methaqualone
peaked around 1980 and has also declined steadily since that time. However, much
counterfeit "lude" is still being sold, but instead of containing methaqualone,
the tablets now often contain diazepam. Diazepam has become the most prevalent
depressant drug of abuse and its use is apparently continuing to rise. It is
somewhat peculiar that of the many benzodiazepines known and readily available
in the legal commercial market, diazepam is by far the most extensively abused.
The factors controlling this apparent user preference for diazepam is certainly
related, in part, to simple product recognition; however, it is my perception
that the dominant factor is the ease with which the drug can be diverted from
the legitimate market. In 1985 the legitimate diazepam market consisted of 5
billion tablets (Franzosa 1985) and since that time generic diazepam tablet
production has increased along with even greater product availability for
diversion into the illicit market (Franzosa, E. personal communication).

A typical benzodiazepine synthesis is not be considered difficult and a
methaqualone synthesis is quite straightforward (Grimmel et al. 1946). Further,
there is a great abundance of literature from which the clandestine chemist can
draw in deciding upon a CsA based upon either the benzodiazepines or
methaqualone itself. However, with the very notable exception of methaqualone,
the clandestine syntheses of depressant drugs in the U. S. have been extremely
rare (Franzosa, E. personal communication). It is not likely that a
clandestinely synthesized benzodiazepine CsA will be encountered as long as the
huge, easily diverted legitimate supplies are at hand.

The use of methaqualone (compound 41, Figure 13) is in decline, but it will
be with us as an abused substance for still some time. Given the very large
numbers associated with the clandestine synthesis of methaqualone, it is perhaps
surprising that only two CsA's of methaqualone (compounds 42 and 43, Figure 13)
have been analyzed at this laboratory. Again, past history would suggest a high
probability for the appearance of new CsA of methaqualone in the future. A CsA
of methaqualone will by necessity have the 3-aryl-quinazoline structure, and as
a result will fall under the CsA amendment. One would shell predict that the
driving force behind any future clandestine synthesis of a methaqualone CsA will
revolve around attempts to use precursor materials which will not alert law
enforcement to the existence of the clandestine laboratory. A literature review
for CsA candidates will quickly surface several possibilities (Boissier and
Piccard 1960; Camillo and David 1960; Jackman et al. 1960; Petersen et al. 1963;
Boehringer Sohn 1968a,b; Sumitomo Chemical Company 1968; Hurmer and Vernin 1968;
Joshi and Singh 1973; 1974). One of the most intriguing methaqualone CsA's from
the perspective of a clandestine chemist would have to be the halo- and thio-
derivatives described by Joshi et al. (1975). Two of the compounds from this
work (compound 44 and 45, Figure 13) possess depressant activity greater than
methaqualone and compound 44 would be particularly well suited to clandestine
synthesis.

Analgesics

Literature covering the analgesics is so voluminous that a review of the
published data on the subject is far beyond the scope of this work. Most of the
potent analgesics are modeled after features found within the structure of
morphine and some literature detailing these structural features has been
published by Paul Janssen (Janssen 1960; 1961; 1962a,b; 1968). Despite a
significant passage of time, the structure activity relationships established in
these works still comprise a very sizable portion of our empirical knowledge on
this subject.

Some 13 years ago, Shulgin (1975) provided a short overview of many of the
known major classes of analgesics. The following constitutes a similar
listing:

Numerous works have dealt with the syntheses and pharmacological testing of
derivatives of the structures listed above. Synthetic procedures have been
improved and refinements aimed at the tailoring of specific analgesics to
fulfill certain medical needs have been addressed. However, it has been since
1975 that no work has been found introducing a new class of analgesics of either
unusual potency or particularly well suited to synthesis in clandestine
laboratories. There has been discovered one compound which may be of minor
interest in that it is an analgesic with potency similar to morphine and can be
described as a ring condensation product of N,N',3-trimethyl-5-hydroxytryptamine
(compound 46, Figure 14) (Brossi 1985). In any discussion of synthetic
anlagesics one must include the so called Bentley compounds. These compounds are
not, in the purest sense, synthetic analgesics as they are C-ring etheno Diels
Alder adducts of thebaine (Bentley et al. 1967a). Etorphine (compound 47, Figure
14) is perhaps the best known compound in the series and has analgesic activity
approximately 1000 times that of morphine (Bentley et al. 1967b; Hutchins et al.
1981). Although reaction conditions appear to be critical, the synthesis of
etorphine derivatives involves what is essentially a two step reaction with
methylvinylketone and an appropriate organometallic reagent (Haddlesey et al.
1972; Hoogsteen and Hirshfield 1983). Hence, the only expected difficulty in the
clandestine synthesis of these compounds would lie in the initial acquisition of
the thebaine. Therefore, it is somewhat surprising that either etorphine or
derivatives thereof have not become a contributor to illicit analgesic supplies.
On the other hand, if etorphine were to be admixed with some less potent
analgesic, such as heroin, it is doubtful that it would ever be detected.

In his 1975 article, Shulgin pointed to meperidine, prodine, and ketobemidone
as possible models for "Drugs of Abuse in the Future." There are some who think
that Shulgin's comments were somewhat of a self fulfilling prophecy as it is
felt that his article is well worn within the circles of clandestine laboratory
operators (Sapienza, F. personal communication). Supporting this premise, at
least to some extent, is the fact that the appearance of the first known
fentanyl, China White, did not occur until 1979 (Henderson, G. 1.. personal
communication). However, it is also the case that desmethylprodine (MPPP;
compound 48, Figure 15) was first encountered in a DEA laboratory sample
submission in July of 1973 (Kram, T. personal communication), a full two years
before Shulgin published his article.

The probability that CsA's of prodine will constitute any appreciable
quantity of the clandestine analgesic market in the future is relatively remote.
The well publicized neuro-toxicity of the prodine dehydration product,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et at. 1983;
Markey et al. 1985; Fries et al. 1986; Parkes 1986), coupled with a limited
scope of derivatives having appreciable analgesic activity (Berger et al. 1947;
Ziering and Lee 1947; Beckett et al. 1957; Loew and Jester 1975) would seem to
remove prodine from consideration as a model for CsA's. The fact that the
3-allyl analog of MPTP is not thought to be neurotoxic (Brossi 1985) and the
corresponding prodine analog has greater analgesic activity than does
betaprodine (Ziering et al. 1957) may be of some interest to the clandestine
laboratory operator. However, allylprodine (compound 49, Figure 15) is already
controlled under Schedule 1. A prodine derivative which may be found in a future
clandestine laboratory is [alpha]-promedol, (Fries and Portoghese 1976).
Analgesic activity for the unresolved stereoisomers of promedol is approximately
ten times that of morphine, but there is some increased difficulty associated
with the synthesis and neurotoxicity for it's MPTP analog is a real possibility.
It is also the case that [alpha]-promedol is listed in CFR Schedule I under the
name of trimeperidine.

In any event, the syntheses of prodine CsA's are fraught with considerable
risk from the inadvertent production of either MPTP or an as yet unexplored
congener also having neurotoxic properties. It is worth noting that at one time
MPTP was tested for use as an insecticide and that there are reports of workers
handling MPTP who have suffered full blown Parkinsonian symptoms (Shafer, J.
personal communication).

Meperidine (pethidine, demerol; compound 50, Figure 16) is approximately 50%
as potent an analgesic as is morphine and has a safety margin of only 4.8 as
compared to 71 for morphine (Janssen 1985) Hence, one would assume that the
continued abuse of meperidine is most probably related to the ease with which it
can be diverted from commercial channels rather than it's applicability to drug
abuse per se. It has been noted that there are some 4000 compounds which may be
related chemically to meperidine (Burger 1970). It should be pointed out that of
these 4000 compounds, many are not classified as analgesics, and they must also
include the closely allied prodine and ketobemidone derivatives. The most potent
analgesics of the meperidine class of compounds, as is the case with the prodine
class of compounds, all appear to already be controlled under Schedule I and the
less potent but clinically useful derivatives controlled under Schedule II. The
most interesting compound from the view point of clandestine synthesis would
have to be phenoperidine (compound 51, Figure 16) as analgesic activity is
approximately 30 times that of morphine and the safety margin is increased,
relative to meperidine, quite substantially (Janssen 1985). Fentanyl (compound
52, Figure 17) is an analgesic of high potency, approximately 300 times that of
morphine, which was developed by Janssen in 1962 (Janssen 1962b) and is
N-[(2-phenylethyl)-4-piperidyl]-N-phenyl-propanamide. The first CsA of fentanyl
came to the attention of law enforcement in late 1979 but was not identified
until 1981 (Allen et al. 1981). In the next three years a procession of new
fentanyl CsA's appeared in the illicit drug market. The abuse of fentanyl CsA's
peaked in 1985 and has since decreased dramatically (Henderson 1987), a
phenomena which was the result of DEA successfully terminating the operation of
the responsible laboratories. However, the ripple effect is still being felt as
international and national meetings have been held to discuss the problems
presented by CsA's. Also, legislation, such as the U. S. CsA amendment, has been
passed in order to allow law enforcement to deal more efficiently with the
analog problem.

It is the author's opinion that fentanyl CsA's will be back as the future
analgesic drugs of abuse. The thoughts behind this statement are that the
published synthesis schemes for the fentanyl compounds allow for the use of wide
variety of precursors as discovered by the confiscated notes from an anonymous
clandestine laboratory that synthesized a drug, based on information presented
in two separate volumes of the Journal of Organic Chemistry (Anon. 1957; Janssen
1962a; Riley et al. 1973; Van Bever et at. 1974; Van Daele et al. 1976). Also,
several fentanyl derivatives have such high potencies that the quantities
required to be synthesized are trivial. For instance, carfentanil (compound 53,
Figure 17) is approximately 400 times as potent as heroin and has an extremely
favorable therapeutic index (Janssen 1985). Hence, an easy week's work for two
chemists could provide 10 kilograms of carfentanil which would be equivalent to
40 metric tons of pure heroin.

Conclusion

In the course of this article, several points have been made concerning those
forces which will control the appearance of future synthetic drugs of abuse. The
most important of these factors is user acceptance of the marketed drug.
Needless to say, the typical clandestine drug dealer and/or chemist is not
overly concerned with the health of the user. However, they are concerned with
having a ready market for their product. A reputation for selling "bad stuff"
would not be conducive to good business. A recent example of this can be found
in MPPP.

The second most important market controlling factor is law enforcement
control of the industry. A recent example would be the effects produced when P2P
was placed under legal controls. The response so far has been two fold; first
there has been a concerted move to either more fundamental precursors or to
synthetic routes utilizing [beta]-hydroxyphenylethylamines, and second, there
has been an apparent increase in the abuse of 4-methylaminorex. Hence, the
methamphetamine market is in a state of flux as a direct result of law
enforcement activity and either a CsA will be found which will provide both the
user and the clandestine drug chemist with the same advantages as
methamphetamine or a new precursor synthesis scheme will be found which will
offer nearly the same advantages as P2P. It is axiomatic that for drugs of
moderate potency and high consumer demand, such as methamphetamine, a synthesis
scheme must be relatively straightforward as it must be amenable to the limited
expertise available in the clandestine laboratories in order to meet consumer
demand.

In this work, only an occasional attempt was made to address the difficulties
associated with the practical synthesis of the various derivatives discussed.
Some of the compounds discussed do not have conveniently configured precursors
that are commercially available. Hence, synthesis of some of these compounds
require using the precursors earth, fire, and water. Additionally, as the number
and complexity of substitution on any given chemical structure increases, there
is a corresponding increase in the number of byproducts and a decrease in the
ultimate yield of target compound. In total then, some of the compounds
mentioned in this work are not practical, especially considering the clandestine
laboratory, given the present state of synthetic knowledge. However, as time
moves on, more efficient and direct methods of synthesis will be found and made
available to the informed reader through the scientific literature. This point
is easily exemplified even by the work of our own forensic scientists (Sy and By
1984; Casale 1987). The clandestine chemist of the future will be more
sophisticated than those of the present and compounds not yet conceived of will
be within their reach.

Consumer preferences and law enforcement activities are the two dominate
forces affecting today's illicit drug markets. While staying within the confines
of consumer demand, the clandestine chemist of the future will synthesize those
drugs having the highest possible potency in an effort to limit his exposure to
law enforcement activities and to expand his illicit business as well.

Acknowledgement: The author wishes to express his appreciation for the
invaluable assistance of Dr. Robert Klein, Ann Wimmers, and Charles Harper in
the preparation of this article.